tbuckley/cabot-search huggingface dataset:
P11.63.B VALIDATING THE NEUROLOGIC ASSESSMENT IN NEURO-ONCOLOGY (NANO) SCALE IN CLINICAL PRACTICE: A MULTI-CENTER PROSPECTIVE STUDY IN PATIENTS WITH GLIOBLASTOMA
Authors: M Lim Fat, R Fox, M Allen, K Roberto, M Machado, H Chen, J Melhem, L Gonzalez Castro, G Youssef, U Chukwueke, J McFaline-Figueroa, E Lee, P Wen, J Perry, D Reardon, L Nayak
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The neurologic assessment in neuro-oncology (NANO) scale was developed as a standardized metric to objectively measure neurologic function in patients with brain tumors and complement radiographic assessment in defining overall outcomes. The scale has been incorporated in clinical trials, however, real-world use of the NANO scale to drive clinical decision-making and the predictive value of the NANO scale to determine overall survival remains unclear in glioblastoma. MATERIAL AND METHODS We report on an ongoing multi-center study of prospective NANO score collection to evaluate neurologic function in patients with glioblastoma, seen at Dana-Farber Cancer Institute (DFCI) and Sunnybrook Health Sciences Center (SHSC). Patient demographics, tumor histology, molecular status, treatment history, and progression dates are being captured. NANO score, Karnofsky performance status (KPS) and corticosteroid dose are collected at prespecified time points (prior to start of therapy, and during each subsequent MRI visit). Changes in the NANO score will be correlated to overall survival and subgroup analyses will be performed for specific domains of the NANO scale. Statistical analyses including descriptive data analysis and generalized linear models will be performed using R (version 3.4.3). RESULTS Since June 2020, 145 patients have been enrolled in this study across the two sites including 90 (62%) with ≥2 follow-up visits. 129 patients had baseline post-operative NANOs captured, with 45 (35%) patients having no deficits in any NANO domain at baseline. All patients with intact baseline NANO had a KPS of 80 or above. Adaptation to a virtual platform for NANO (vNANO) allowed for improved recruitment and follow-up of patients. Validation of vNANO is being performed in a subset of this population. Our interim analysis will be presented at the 2023 EANO meeting. CONCLUSION Evaluation of neurologic function by NANO is feasible in both an in-person and virtual framework in a prospective multi-center study in patients with glioblastoma. NANO is able to objectively track neurologic function throughout disease course in glioblastoma. Integration of vNANO may allow for reduced clinical visits and improve access to specialized care for patients in geographically remote locations.
P04.02.A CEREBELLAR GLIOMA WITH BRAF ACTIVATION: A MOLECULARY DISTINCT GLIOMA SUBGROUP WITH MAPK ACTIVATION
Authors: F Hinz, L Schweizer, A Reinhardt, D E Reuss, M Sill, O Witt, S M Pfister, D T W Jones, A von Deimling, F Sahm
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Rendering the correct tumor diagnosis is key to optimise cancer therapies and to orient patients and relatives regarding prognosis and general understanding of the disease. With the rising impact of molecular diagnostics more molecular profiles of tumors are being generated and assembled in central institutes. With this critical data assembly in world-wide repositories such as www.molecularneuropathology.org, new tumor groups with differing prognosis and driver alterations can be discerned. MATERIAL AND METHODS By analysing the epigenetic profiles from over 125.000 CNS tumor samples a distinct group of cases was identified (n=24). The samples in this group did not match an established reference methylation class in the Heidelberg brain tumor classifier (version 12.5). In a first analysis with the clinical data external suppliers have provided, these tumors are located in the cerebellum and typically in children (mean age = 9 years). RESULTS The variable histology ranged from low grade glial/glioneuronal appearances such as pilocytic astrocytoma (n= 12), ganglioglioma (n= 4), gangliocytoma (n= 1) to ependymoma (n= 2) and anaplastic ependymoma (n=1). For some cases just a descriptive histopathological diagnosis could be rendered (n= 6). A prominent feature in radiology and histology were micro- and macrocalifications (n =5). From 24 cases, 17 tumors (89% of all analysed tumors) harboured a BRAF V600E mutation. One case revealed a PRKAR2B:BRAF fusion. 6 cases could not be analysed because no remaining tumor material was available. While clinical follow-up data collection is still maturing, relapses were reported in 2 patients, and stable disease was reported in 12 cases. For 10 cases no follow up data is available, yet. CONCLUSION We found an epigenetically distinct group of childhood brain tumors located in the posterior fossa with an enrichment of BRAF V600E mutations. Clinical follow-up is yet to be evaluated, but recurrence was observed in a proportion of patients with available follow-up.
P11.25.A TUMOR TREATING FIELDS (TTFIELDS) REAL-WORLD EXPERIENCE IN NEWLY DIAGNOSED GLIOBLASTOMA: A SYSTEMATIC LITERATURE REVIEW AND META-ANALYSIS OF OVERALL SURVIVAL
Authors: M T Ballo, P Conlon, G Lavy-Shahaf, A Kinzel, J Vymazal, A M Rulseh
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Tumor Treating Fields (TTFields) are electric fields that disrupt processes critical for cancer cell viability and tumor progression by a multi-modal mechanism of action. TTFields therapy is FDA-approved for newly diagnosed glioblastoma (ndGBM) based on results from the randomized, phase 3 EF-14 study (NCT00916409). We assessed the overall survival (OS) benefit of adding TTFields therapy to standard of care (SOC) for patients with ndGBM treated in clinical practice, as well as the relationship between OS and device usage rate. MATERIAL AND METHODS A systematic literature review (PubMed, Embase, and Cochrane Library) identified single-cohort and comparative clinical studies that assessed survival in patients with ndGBM who received TTFields therapy. Inter-study heterogeneity was quantified using the Higgins I2 statistic and Cochran Q test. A distribution-free random-effects method was used to pool survival curves. RESULTS Nine studies were identified that evaluated survival with TTFields therapy in ndGBM. Of these, the 7 studies (1430 patients) that compared TTFields therapy with SOC to SOC alone were included in a pooled analysis for OS. The pooled data showed significantly longer OS with TTFields therapy/SOC vs SOC alone (hazard ratio [HR]: 0.63; 95% CI, 0.53-0.75; P&amp;lt;0.001). A sensitivity analysis indicated that the effect was robust and independent of any individual study. In post-approval studies, pooled median OS was 22.2 months (95% CI, 17.3-42.6) for TTFields therapy/SOC and 17.3 months (95% CI, 13.6-22.0) for SOC alone. Gross total resection was generally more prevalent in the real-world setting, irrespective of TTFields use. Among studies evaluating device usage, an average usage rate of ≥75% was associated with prolonged OS vs &amp;lt;75% usage (pooled HR: 0.60; 95% CI, 0.48-0.73; P&amp;lt;0.001). CONCLUSION Pooled analysis of comparative TTFields therapy studies suggests a significant survival benefit with TTFields added to SOC for patients with ndGBM, and that a recommended 75% usage rate may be clinically meaningful in the real-world setting.
P11.85.B LONG-TERM OUTCOME AFTER INCOMPLETE RESECTION OF INTRAMEDULLARY GRADE II EPENDYMOMAS WITHOUT ADJUVANT RADIOTHERAPY
Authors: E Chaskis
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Ependymomas are the most frequent intramedullary tumors in adults. While gross total resection is the aim of surgery, tumor infiltration might limit resection. In case of subtotal removal, the adjuvant management remains unclear. The aim of our study was to assess the need for adjuvant radiotherapy after incomplete resection of grade II intramedullary ependymomas (IME-II). MATERIAL AND METHODS We retrospectively reviewed all cases of IME-II operated in a single tertiary neurosurgical center from 2009 to 2018. Patients with anaplastic or myxopapillary ependymomas, and patients with a follow-up of less than 3 years were excluded. RESULTS We included 46 patients: 19 (41.3%) had gross total resection, 21 (45.7%) had subtotal resection and 6 (13%) had partial resection. None of the patients underwent adjuvant radiotherapy. Over a median follow-up of 79 months (range = 36-186), 7 patients presented a radiological tumor progression with a mean delay of 50.9 months (range =18-85), of which 2 were symptomatic (4.3%). Progression-free survival (PFS) was 90.1% at 5 years and 76.8% at 10 years. Extent of resection was the only significant risk factor for secondary tumor progression (p=0.012). 4 of the 7 patients with recurring IME-II were treated: 3 patients had a second surgery, leading to 2 GTR and 1STR, followed by radiotherapy in one case, and 1 patient underwent radiotherapy alone. CONCLUSION In this study, the rate of symptomatic progression and retreatment after incomplete resection of IME-II without adjuvant radiotherapy was low, supporting a conservative approach in such cases.
P11.81.B PRELIMINARY RESULTS FROM A RETROSPECTIVE STUDY OF AWAKE CRANIOTOMIES WITH INTRAOPERATIVE MAPPING IN YOUNG ADULTS WITH GLIOMA
Authors: A B Kønig, C M Engelmann, J Skjøth-Rasmussen
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Awake craniotomy with intraoperative mapping (ACWM) has been proven beneficial in achieving maximal resection of gliomas in eloquent brain areas while preserving neurological function, thus maintaining onco-functional balance. The present study aimed to describe the intraoperative symptoms not related to resection induced deficits in young adult glioma patients during ACWM. METHODS A retrospective, descriptive study of young adults (18-39 years of age) with glioma operated with ACWM in Copenhagen between 2016 and 2022. Patients were identified using the hospital operation booking system cross-referenced with the patient coding system. All data was available in and extracted from the Epic Systems healthcare software used at the hospital. RESULTS So far 37 patients with glioma (median age 31 years, range 21-39 years; 51% females; 78% high-grade gliomas) have been included, constituting 46 planned ACWMs. Most patients (95%) reported some level of intraoperative pain and/or headache with 27% receiving supplemental local anesthetics and 63% receiving supplemental fentanyl or fentanyl analogues during the awake phase. The median for the immediate postoperative Numeric Pain Rating Scale was 1, range 0-7. Intraoperative non-localization specific symptoms included shivering (41%), fatigue (22%), nausea/vomiting (17%), emotionally overwhelm (15%), anxiety (5%) and postoperative vasovagal syncope (5%). Focal seizures were reported in 24% of patients while 1 patient was untimely converted to general anesthesia due to non-convulsive status epilepticus. Operations were terminated due to completed macro-radical resection (32%), reaching the functional limit of resection (63%) and severe fatigue (5%). CONCLUSION Our results represent the practice of a single institution and comply well with previous literature in terms of symptomatic complications not related to resection induced deficits. These symptoms are predominantly simple to manage without the need for untimely termination of surgery. Awake craniotomy with mapping is deemed well-tolerated by young adults and is considered beneficial in optimizing the onco-functional balance of selected glioma patients.
P02.15.A PRONEURAL, CLASSICAL AND MESENCHYMAL PROTEIN SIGNATURES LACK PROGNOSTIC VALUE IN WHO 2021 ADULT TYPE DIFFUSE LOWER-GRADE GLIOMAS
Authors: A Dénes, T Olsson Bontell, H Barchéus, S Ferreyra Vega, H Carén, C Lindskog, A S Jakola, A Smits
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Mesenchymal transformation in glioblastomas is associated with therapy resistance and increased aggressiveness. In WHO 2021-defined adult-type diffuse gliomas of lower grade (dLGG), the transition between phenotypic states, has not been studied. Most reports correlating proneural, classical or mesenchymal signatures with outcome in dLGG were made prior to the WHO 2021 classification. Here, we set out to investigate if phenotype as well as the transition of phenotype predicted survival in a clinical cohort of WHO 2021 defined dLGGs. MATERIAL AND METHODS We used a TMA-based approach and five immunohistochemical markers (EGFR, p53, MERTK, CD44 and OLIG2) to examine 183 primary and 49 recurrent tumors from patients with previously diagnosed dLGG. Of the 49 recurrent tumors, nine tumors relapsed a second time, and one a third time. RESULTS In total, 71.0% of all tumors could be subtyped into proneural, classical or mesenchymal. Proneural was the predominant subtype among IDH-mut tumors (78.5%), while in IDH-wt tumors mesenchymal was more common (63.6%). A significant difference in survival was found between subtypes (proneural, classical and mesenchymal) in the total cohort (p&amp;lt;0.001), but not when molecularly stratified (IDH-mut: p=0.220, IDH-wt: p=0.623). Upon relapse, proneural signature was retained in 66.7% of the proneural IDH-mut dLGGs (n=21), whereas IDH-wt tumors (n=10) mainly retained or gained mesenchymal phenotype. There was no significant difference in survival between IDH-mut gliomas remaining proneural and those switching to mesenchymal signature (p=0.347). CONCLUSION Subtyping into proneural, classical and mesenchymal phenotypes by five immunohistochemical markers, was possible for the majority of tumors, but statistical significance between phenotypes and survival was lost after molecular stratification according to the WHO 2021 criteria. IDH-mut tumors mainly remained proneural at recurrence, while IDH-wt tumors mostly retained or gained mesenchymal phenotype. This phenotypic shift, which in glioblastoma is associated with increased aggressiveness, did not affect survival. Sample sizes were, however, too small to draw any firm conclusions on whether this negative finding is due to lack of statistical power or reflects a true biological difference from glioblastomas.
P10.03.A ANTIPSYCHOTICS TO TREAT BRAIN TUMORS: DRUG REPURPOSING TO BYPASS THE BLOOD BRAIN BARRIER
Authors: T Wikerholmen, E M Taule, E Rigg, M Sættem, K Sarnow, T Hoang, H S Saed, T Sundstrøm, F A Thorsen
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Approximately half of late-stage melanoma patients develop brain metastases (BM), once metastasized to the brain, survival is generally measured in months. Current treatments, although increasingly effective, are not sufficient for this patient group, necessitating development of new therapeutic options. Drugs targeting BM specifically are a scarcity. To broaden therapeutic options, drug repurposing, i.e. novel uses of drugs already approved for other medical conditions, may prove to be a valuable asset. By design, antipsychotics effectively cross an intact blood-brain barrier. Interestingly, although carrying an increased burden of comorbidity, the schizophrenic population has a similar incidence of cancer when compared to the normal population. Hypotheses regarding the antitumor effect of antipsychotics have therefore been postulated along with several other theories that seek to explain these seemingly contradictory incidence rates. We currently present preliminary data showing that clozapine, a second-generation antipsychotic, effectively inhibits growth of human melanoma brain metastasis (MBM) cell lines in vitro. Objective: To explore the potential of antipsychotics in treating MBM. METHODS Cell cultures including H1, H2, H3 MBM cell lines, as well as normal human astrocytes (NHA) were selected for our experiments. Monolayer, 3D, and IncuCyte viability experiments were performed to determine IC50 doses. FBRO, fetal rat brain organoids were used to study clozapine’s effect on the normal brain environment. Cell migration was measured by scratch wound assays. Apoptosis was studied by flow cytometry. Colony formation assays were performed using 2D clonogenic assays. A protein array was used to find signaling proteins potentially affected by clozapine, which where verified by western blots. RESULTS A viability screening using 6 different neuroleptics showed that clozapine was most effective in inhibiting MBM cell viability, with a favorable therapeutic window to astrocytes. Doses significantly above MBM IC50 doses did not affect viability of brain organoids. MBM cells exhibited a dose-dependent inhibition of cell proliferation, migration, and clonogenic formation. Flow cytometry demonstrated that apoptosis was a major mechanism of cytotoxicity. The protein array showed that CCL3, IL8 and VEGF were downstream targets of clozapine. These results were confirmed by western blots. A partnership with the Dept. of Chemistry (UiB) has resulted in the development and testing of several novel clozapine derivates to reduce therapeutic doses and hopefully minimize potential side effects. CONCLUSION Clozapine shows proof of concept in treating BM with antipsychotics and should be explored further as an adjuvant treatment for melanoma patients at risk of developing brain metastasis.
P11.64.A TREATMENT STRATEGIES BEFORE THE DIAGNOSIS OF BRAIN METASTASIS IN PATIENTS WITH RENAL CELL CANCER (RCC)
Authors: S H A E Derks, E L van der Meer, A Joosse, M de Jonge, C Slagter, J W Schouten, E Oomen-de Hoop, M Smits, M J van den Bent, J L M Jongen, A A M van der Veldt
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Metastatic renal cell cancer (mRCC) is known for its variable disease course and can be categorized according to the International Metastatic RCC Database Consortium (IMDC) criteria. As patients with mRCC who have a favorable IMDC score and/or a low tumor burden usually have an indolent disease course, watchful waiting is often considered in daily clinical practice. However, it is unknown whether watchful waiting impacts the development of brain metastasis (BM). Therefore, we investigated variables that may affect the interval between first diagnosis of mRCC and BM (BM-free interval) in patients with RCC and BM. MATERIAL AND METHODS A single-center, retrospective cohort study was performed at the Erasmus MC Cancer Institute (Rotterdam, the Netherlands). All consecutive patients with a diagnosis of RCC and BM between 01-01-2011 and 31-07-2022 were included. The primary outcome was the BM-free interval. Secondary outcomes were intracranial progression-free survival (iPFS), progression-free survival (PFS) and overall survival (OS), since diagnosis of BM. Subgroups included patients with and without systemic treatment prior to the diagnosis of BM. Kaplan-Meier (Logrank test) and Cox Proportional Hazards Model (Likelihood ratio test) analyses were performed with significance considered at p-values &amp;lt;0.05. RESULTS A total of 46 patients with RCC and BM were included; 80% was male and 89.1% had a clear cell RCC subtype. In 84.8% of patients, BMs were diagnosed metachronous (&amp;gt;1 month) after the diagnosis of extracranial metastasis (ECM) and 80.4% of patients had symptomatic BM at BM diagnosis. After the diagnosis of BM, the median iPFS was 7.6 (IQR 3.5-12.2) months, the median PFS was 3.7 (IQR 2.3-8.7) months and the median OS was 10.1 (IQR 5.1-22.8) months. Prior to the diagnosis of BM, 25 (54.3%) patients had received systemic therapy, whereas 21 (45.7%) patients were treatment naïve. The median BM-free interval was 22.3 (IQR 5.7-46.7) months. The median BM-free interval was significantly shorter for treatment naïve patients (6.8 [IQR 1.0-7.0] months) as compared to patients who received previous systemic therapy (29.0 [IQR 12.6-57.0]; p=0.02). In multivariate analysis, a longer BM-free interval was significantly associated with nephrectomy (HR 0.10 [95%CI 0.03-0.31]) and systemic treatment prior to BM diagnosis (HR 0.10 [95%CI 0.03-0.30]). CONCLUSION In this cohort of patients with RCC BM, patients who had not received systemic treatment for ECM were earlier diagnosed with BM than patients who had received prior systemic treatment. Although the retrospective nature of this small selective cohort is a limitation, these results indicate that watchful waiting should be carefully considered for patients with mRCC.
P19.01.A INVESTIGATING THE MORPHOLOGICAL HETEROGENEITY OF GLIOBLASTOMA STEM CELLS AND ITS ROLE IN TUMOUR PROLIFERATION AND INVASIVENESS
Authors: C Barelli, F Kaluthantrige Don, I Bertani, G Villa, I Osei, R Iannuzzi, A Vinceti, E Brognaro, A Sottoriva, F Iorio, N Kalebic
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma is the most common and aggressive primary brain tumour. Cancer hijacks developmental pathways and several studies have identified a stem cell-like population in glioblastoma following neurodevelopmental trajectories. In the foetal neocortex, a type of neural stem cell called basal progenitor is thought to be responsible for neocortical expansion. Basal progenitors exist in different morphotypes, and greater morphological complexity underlies their increased proliferation. We thus propose that cell morphology also plays a role in the proliferation and invasiveness of glioblastoma stem cells. MATERIAL AND METHODS We characterise the morphological heterogeneity of glioblastoma stem cells by immunostaining of human primary bulk tumour and peritumoral tissue. To then understand the function of cell morphology in tumour progression, we genetically manipulate morpho-regulatory molecules in 2D glioblastoma stem cells that show a genetic dependency on the target molecules based on cancer dependency maps. RESULTS We show that glioblastoma stem cells have a vast morphological heterogeneity in human primary bulk tumour and peritumoral tissue. The morphotypes observed are conserved in 2D glioblastoma stem cells and they are reminiscent of neural progenitors in the developing neocortex. We then test whether the genetic manipulation of those morpho-regulatory molecules which control the proliferation of basal progenitors in the fetal neocortex also affects the proliferation and invasiveness of glioblastoma stem cells. CONCLUSION Glioblastoma stem cells display extensive morphological heterogeneity, like basal progenitors in the developing neocortex. Morpho-regulatory molecules do not only control cell shape but may contribute to the proliferation and invasiveness of glioblastoma stem cells. We envision that the identification of morpho-regulatory molecules controlling tumour progression will open new therapeutic windows through pharmacological targeting and drug repurposing.